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Interleukin-8 Expression Is Regulated by Histone Deacetylases through the Nuclear Factor-B Pathway in Breast Cancer

Institut National de la Santé et de la Recherche Médicale, U844, and University of Montpellier I, Montpellier, France (C.C., C.B., A.F., S.D., C.Jor., G.L.); and Department of Medicine, Pharmacology, and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (M.M., C.Job.)

We have reported recently that the chemokine interleukin 8 (IL-8)/CXCL8 was overexpressed in invasive estrogen receptor (ER)-negative breast cancer cells compared with ER-positive breast cancer cells. We now demonstrate that histone deacetylases (HDACs) play an essential role in the regulation of IL-8 gene expression in ER-positive MCF-7 breast cancer cells. Treatment of MCF-7 cells with the HDAC inhibitor trichostatin A (TSA) led to a strong up-regulation of IL-8 protein and RNA levels in MCF-7 cells. The up-regulation of IL-8 in MCF-7 cells was time- and concentration-dependent. Moreover, run-on and transfection experiments demonstrated that IL-8 induction by HDAC inhibitors was transcriptional and involved mainly the nuclear factor-B (NF-B) site of the IL-8 promoter. These observations are corroborated by an up-regulation of NF-B activity in MCF-7 cells in the presence of TSA. In addition, blocking NF-B pathway by adenoviral delivery of a dominant-negative IBorIB kinase complex 2 (IKK2) mutant abolished IL-8 gene induction by histone deacetylase inhibitors. HDAC inhibitors triggered IKK phosphorylation and up-regulated p65 nuclear translocation, although they decreased the protein levels of IB, which accounts for NF-B activation. TSA increased binding of acetylated histone 3 to the IL-8 gene promoter. In summary, our results demonstrate that NF-B pathway repression by HDAC is responsible for the low expression of IL-8 in ER-positive breast cancer cells.

Address correspondence to: Dr. Gwendal Lazennec, INSERM, U844, Site Saint Eloi-Bâtiment INM, 80, rue Augustin Fliche, 34091 Montpellier cedex 5, France. E-mail: Gwendal.Lazennec{at}inserm.fr